Fibrosis is generally defined as the development of extra connective tissue as part of the healing process and includes a diverse set of symptoms. Excessive fibrosis is a grievous problem that has few therapeutic options.
Cystine knot-containing proteins are typically important regulators of key functions and affect diverse cell types. Wise (USAG-1, SOSTDC1) is a secreted, cystine knot-containing protein and is expressed primarily in the kidney, lungs and epithelial cells. WISE KO mice are fertile and their kidneys have normal function. However when challenged to develop kidney injury either by unilateral ureteral obstruction (UUO) or injection of chemotoxic agent Cisplatin, the WISE KO mice are protected (Yanagita et al., J. Clin Invest. 2006 Jan. 4; 116(1): 70-79). In the UUO model, there is much less fibrosis in the affected kidney in WISE KO mice and expressed much less aSMA, a marker of myofibroblast activation, and preserved the expression of epithelial cell marker E-cadherin. In a Cisplatin model for kidney injury, WISE deletion protected the animal from tubular injury and reduced mortality (Tanaka et al., Kidney International advance online publication 17 Oct. 2007). In addition, when WISE KO mice (aka USAG-1 KO mice) were breed with Co14a3 KO mice, the double knockout mice had significantly less proteinuria and developed less end stage renal disease relative to the Co14a3 KO mice with WT WISE gene. At 4 weeks of age, USAG-1+/+, 3(IV)−/− mice already showed severe proteinuria with extensive splitting of glomerular basement membrane (GBM), while double KO mice showed normal structure of GBM. At 10 weeks of age, USAG-1+/+, 3(IV)−/− mice developed end-stage renal disease, while double KO mice showed significantly preserved renal function with less renal histological changes. (Abstract TH-FC059 2008 ASN meeting).
These data suggest that WISE could be a regulator of adult kidney function. However these studies were limited to knock out mice lacking WISE for their entire development cycle, accordingly it was unpredictable whether acute inhibition of WISE activity using an inhibitor such as an antibody could provide therapeutic benefit to preserve kidney function under pathological conditions associated with various fibrotic diseases.
The present inventors demonstrate it is possible to treat lung and kidney disorders associated with damage and repair including fibrosis and organ dysfunction using binding agents that target WISE.